The interaction of MCI-154, a calcium sensitizer, and isoflurane on systemic and coronary hemodynamics in chronically instrumented dogs

We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia. IMPLICATIONS: MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.     

Hemodynamic interactions of propofol and dantrolene in chronically instrumented dogs

The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia. IMPLICATIONS: Our study suggests that dantrolene reverses the hypotensive action produced by propofol and causes an increase in coronary blood flow with a decrease in coronary vascular resistance, but does not significantly change the negative inotropic effects.     

Proteasome expression in the skeletal muscles of patients with muscular dystrophy

Previous investigators have suggested that proteolysis by calpain, a Ca²⁺-dependent protease, causes muscle fiber degradation in Duchenne and Becker muscular dystrophies (DMD/BMD). Recent evidence indicates that the nonlysosomal ATP-ubiquitin-dependent proteolytic complex (proteasomes) participates in muscle wasting during various catabolic states and in muscle fiber degradation in physiological or pathological conditions. To elucidate the possible role of proteasomes in dystrophic muscles, routine histochemistry and immunohistochemistry of 26S proteasomes were performed on muscle biopsy specimens obtained from patients with various neuromuscular disorders including DMD/BMD, polymyositis (PM), amyotrophic lateral sclerosis, and peripheral neuropathies, and on normal human muscle specimens. Immunohistochemically, proteasomes were located in the cytoplasm in normal human muscle, but their staining intensity was faint. Compared to control muscles, abnormal increases in both proteasomes and ubiquitin were demonstrated mainly in the cytoplasm of necrotic fibers and to a lesser extent in regenerative fibers in DMD/BMD and PM. Non-necrotic, atrophic fibers in all diseased muscles showed moderate or weak immunoreactions for the proteins; their staining intensities were stronger than those of control muscle fibers. Both proteins often colocalized well. Not all dystrophin-deficient muscle fibers showed a strong reaction for proteasomes. Our results showed increased proteasomes in necrotic and regenerative muscle fibers in DMD/ PMD, although this may not be disease-specific up-regulation. We suggest that the ATP-ubiquitin-dependent proteolytic pathway as well as the nonlysosomal calpain pathway may participate in muscle fiber degradation in muscular dystrophy. Received: 9 July 1999 / Revised: 28 December 1999, 21 February 2000 / Accepted: 21 February 2000     

Genetic polymorphism of COX-1 gene and NSAID-induced ulcer

Cyclooxygenase-1(COX-1) has traditionally been regarded as a constitutively expressed enzyme that generates prostaglandins for gastrointestinal integrity. The effects of non-steroidal anti-inflammatory drug(NSAID) on the gastric mucosal damage are caused by the inhibition of this enzyme. Although A-842G in the COX-1 gene promoter was reported as a functional polymorphism, we could not detect this polymorphism in Japanese population. However, T-1676C polymorphism (rs1330344) was significantly associated with the development of peptic ulcer, especially gastric ulcer. In addition, rs1330344 was also significantly associated with the development of NSAID-induced ulcer diseases. In conclusions, the assessment for genotype of COX-1 gene promoter polymorphism, especially rs1330344, may be useful for detecting the high risk group of developing NSAID-induced ulcer diseases.     

Promoter hypomethylation of protease-activated receptor 2 associated with carcinogenesis in the stomach

BACKGROUND AND AIM: Trypsin acting at protease-activated receptor 2 (PAR2) contributes to a progression of malignant tumors. An abnormal DNA methylation has been recognized as an important molecular mechanism for the genesis of various types of cancers. We attempted to clarify the relationship between the promoter methylation of PAR2 and gastric cancer. METHOD: We estimated the methylation of the PAR2 promoter in both antral non-cancerous mucosa and cancer lesions in 94 patients with gastric cancer. We employed a methylation-specific PCR method. RESULTS: Regarding the methylation ratio (MR) of antral-non-cancerous mucosa, no significant difference was despite among gender, age and Helicobacter pylori infection status, whereas MR increased rising inflammation scores. The MR of cancer lesions was significantly lower than that of antral non-cancerous mucosa. This finding was not dependent on tumor staging, but also histological classification. In venous invasion, lymph node metastasis, or peritoneal dissemination negative cases, this significant lower MR was also seen. CONCLUSION: The promoter methylation of PAR2 seems to be increased with a progression of chronic inflammation and has an inhibitory effect on carcinogenesis of the stomach.     

Effect of polymorphisms of IL-1β and TNF-α genes on CpG island hyper methylation (CIHM) in the nonneoplastic gastric mucosa

CpG island hyper methylation (CIHM) is one of the major events in gastric carcinogenesis. To evaluate the influence of host genetic factors in CIHM related carcinogenesis, we investigated the association between common polymorphisms in IL-1β and TNF-α genes, with CIHM status in the nonneoplastic gastric mucosa. Polymorphisms in the IL-1β gene (-31T>C and -511C>T) and the TNF-α gene (-857C>T) were genotyped in 385 cancer-free subjects. CIHM of four candidate genes: p16 (INK4a), p14 (ARF), E-cadherin (CDH1), and death-associated protein kinase (DAP-kinase), were determined by methylation-specific-polymerase chain reaction (MSP). CIHM high was defined as two or more CpG islands methylated. CIHM of all four genes and CIHM high were significantly associated with Helicobacter pylori infection status. In over all, significant marginal association was found between IL-1β-511 TT genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.48, 95% CI = 0.29-0.78) and CIHM high (adjusted OR = 0.53, 95% CI = 0.32-0.86). This association was more enhanced in subjects 65 yr or younger age. We also found positive association between TNF-α-857T carrier and increased susceptibility to CIHM of CDH (adjusted OR = 1.78, 95% CI = 1.01-3.16), and CIHM high (adjusted OR = 1.86, 95% CI = 1.04-3.33) in the same generation. The mean number of CIHM was lower in subjects with IL-1β-511TT genotype, while the mean number was higher in subjects with TNF-α-857 T carrier especially in subjects 65 yr and younger patients. IL-1β-511 TT genotype is associated with reduced susceptibility to CIHM especially in younger generation. Furthermore, the TNF-α-857T carrier is associated with increased susceptibility of CIHM in the same generation.     

Toll-like receptor 2 -196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer

Toll like receptors (TLR) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. The –196 to –174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of the TLR2 –196 to –174del polymorphism on the occurrence of non-cardiac gastric cancer (NCGC) in a Japanese population. The study was carried out with 289 patients with NCGC, 309 non-cancer patients with abdominal discomfort and 146 healthy controls. The –196 to –174del TLR2 polymorphism was investigated using the allele-specific polymerase chain reaction method in all of the subjects. The –196 to –174del/del genotype of TLR2 showed a significantly higher frequency in NCGC patients than in healthy controls (adjusted odds ratio [OR] = 6.06; 95% confidence interval [CI] = 1.86–19.72). Similarly, the frequency of the –196 to –174del/del genotype was significantly higher among NCGC patients than in non-cancer patients (adjusted OR = 2.02; 95% CI = 1.22–3.34). The same genotype was associated with an increased risk of both intestinal (OR = 2.00, 95% CI = 1.12–3.60) and diffuse-type (OR = 2.05; 95% CI = 1.11–3.79) histopathology. There were no significant associations between TLR2 genotypes and tumor stage and anatomical location. Our data suggest that the –196 to –174del/del genotype of TLR2 may increase the risk of gastric cancer in the Japanese population. ( Cancer Sci 2007; 98: 1790–1794)     

Validity of recommended minimum dose of prior morphine to initiate transdermal fentanyl patch in prescribing information - multicenter survey of on prescriptions by palliative care specialists in Japan

For initiating the minimum-size (0.25 microg/hour) transdermal fentanyl patch (TDF), 45 mg a day of oral morphine is the recommended minimum dose (RMD) in Japan according to the prescribing information. However, little is known about the validity of the RMD, and we can presume there are many cases where clinicians are inclined to initiate the minimum-size TDF at the early stage contrary to the RMD due to the high morbidity rate of digestive system cancer in Japan. In order to verify the validity of the RMD, we collected 71 retrospective cases where the minimum-size TDF was initiated against the restriction of RMD. The prior morphine (or equivalent doses of other opioids) was prescribed by palliative care specialists at 5 facilities which belong to Symptom Control Research Group (SCORE-G). Then, the side effects and pain control from the 1st to the 4th day were analyzed. The mean age of subjects was 68, and the main reason for initiating TDF therapy was gastrointestinal symptoms (63.4%). The frequency of side effects such as somnolence, nausea, vomiting and constipation did not show a significant correlation with the prior opioid dose.However,severe dyspnea and respiration depression were documented in two patients, and the above rate was three times higher than the nationwide result of the same side effects (0.9 8%). According to the Numeric Rating Scale (from 0: no pain to 10: the worst pain), the pain intensity decreased from 6.6 on the 1st day to 2.8 on the 2nd day, 3.3 on the 3rd day, and 2.9 (p < 0.001) on the 4th day. We conclude that, although introducing the minimum-size TDF against the RMD served to decrease the pain intensity,it raised the side effects on the respiratory system even when prescribed by palliative care specialists. Therefore,the RMD regulation is valid for general practitioners from a medical safety standpoint.